An increased production of hormones by the adrenal glands is responsible for a variety of clinical conditions in man and other animals. Prolonged exposure of every tissue in the body to an excess of cortisol produces Cushing's syndrome (CS). Endogenous causes of Cushing's syndrome are (1) adrenocorticotropin (ACTH)-dependent, including Cushing's disease—the hypercortisolism that results form the excessive secretion of corticotropin (ACTH) by a pituitary adenoma, ectopic ACTH-producing tumours. Corticotropin releasing hormone (CRH)-producing tumours, and (2) ACTH-independent Cushing's syndrome, including cortisol-producing adrenal benign or malignant tumours, and rare adrenal hyperplasia. The incidence of ACTH-dependent Cushing's syndrome due to endogenous causes is about 60%, in which autonomous pituitary ACTH secretion is responsible for 95%, and the rest are ectopic ACTH-producing tumours. Cortisol-secreting tumours are responsible for about 40% of endogenous causes, in which benign adenoma is 90% and adrenocortical carcinoma is approximately 10%.
The classical symptoms of Cushing's syndrome include central (abdominal) weight gain and a typical change in appearance, thinning of the skin, muscle weakness, amenorrhoea, polyuria and polydipsia, insulin resistance, hypertension, depression, psychosis and insomnia. In addition patients with chronic hypercortisolaemia due to Cushing's syndrome may exhibit cognitive dysfunction in a pattern similar to that seen in Alzheimer's disease (Starkman M N et al Biol Psychiatry 1992 Nov. 1; 32(9):756-65). Many of the changes seen in Cushing's syndrome are very similar to those seen in the aging process. This has led some to postulate that a raised cortisol level, or an altered responsiveness to glucocorticoids, is responsible, at least in part, for the changes seen in the elderly. It has been suggested that many of the changes seen in the aging process are a form of “pseudo-Cushing's disease”.
In a study by Van Cauter et al (J Clin Endocrinol Metab 1996 July; 81 (7):2468-73), a total of 177 temporal profiles of plasma cortisol from normal individuals (90 men and 87 women), aged 18-83 years, were analyzed. Twelve parameters quantifying mean levels, value and timing of morning maximum and nocturnal nadir, circadian rhythm amplitude, and start and end of quiescent period were calculated for each individual profile. In both men and women, mean cortisol levels increased by 20-50% between 20-80 years of age. Premenopausal women had slightly lower mean levels than men in the same age range, primarily because of lower morning maxima. The level of the nocturnal nadir increased progressively with aging in both sexes. An age-related elevation in the morning acrophase occurred in women, but not in men. The diurnal rhythmicity of cortisol secretion was preserved in old age, but the relative amplitude was dampened, and the timing of the circadian elevation was advanced. They concluded that there are marked gender-specific effects of aging on the levels and diurnal variation of human adrenocorticotropic activity, consistent with the hypothesis of the “wear and tear” of lifelong exposure to stress. They suggested that the alterations in circadian amplitude and phase could be involved in the etiology of sleep disorders in the elderly. However, the rise in cortisol levels may not be a universal feature in the elderly as indicated by the study from Lupien et al (Neurobiol Aging 1996 January-February; 17(1):95-105) in which a group of 51 healthy elderly volunteer subjects participated in a 3- to 6-year longitudinal study of basal cortisol levels. Cortisol levels were shown to increase with years in one subgroup, to decrease in another, and to remain stable in a third. However, in patients who showed a rise in cortisol levels with time there was a positive correlation between the response to an obsession/compulsion questionnaire and the rate of rise of cortisol. These authors concluded that their results were consistent with animal studies showing the existence of subpopulations of aged rats which differ in hypothalamo-pituitary-adrenal activity and cognitive efficiency.
Not only do cortisol levels tend to rise with age but the circadian rhythm of cortisol production is also disturbed with the passage of years. Milcu et al (Endocrinologie 1978 January-March; 16(1):29-39) examined the circadian rhythms of plasma cortisol in 25 persons aged between 70 and 100 years and compared them with 5 persons aged between 17 and 38 years. The results showed that the circadian rhythm in plasma cortisol changes with age. The characteristic phenomena found were a tendency towards reducing the hourly quantitative differences, comparatively more marked between 90 and 100 years; anticipation of the cortisol maximum level of 08.00 hours at 04.00 hours in the group of 71 to 80 years, and at 00.00 hours in some of the subjects older than 80. A normal circadian rhythm was found in 2 of the 25 cases examined. The changes in the circadian rhythms of cortisol showed that the regulation systems are also impaired in the aging process. It is possible that early-morning insomnia of the aged may be due to this anticipation in cortisol secretion
Because glucocorticoid excess is associated with hippocampal damage in animals, and the hippocampus participates in learning and memory, the relationships between hippocampal formation (HF) volume, memory dysfunction, and cortisol levels was explored in 12 patients with Cushing's syndrome. After magnetic resonance imaging, HF volume was determined using digital sum of track ball traces of denrate gyrus, hippocampus proper and subiculum, correcting for total intracranial volume. For 25% of the patients, HF volume fell outside the 95% confidence intervals for normal subject volume given in the literature. In addition, there were significant and specific correlations between HF volume and scores for verbal paired associate learning, verbal recall, and verbal recall corrected for full-scale IQ (r=0.57 to 0.70, p<0.05). HF volume was negatively correlated with plasma cortisol levels (r=−0.73, p<0.05). These studies suggest an association between reduced HF volume, memory dysfunction, and elevated cortisol in patients with CS.
Thus, the changes seen in patients with CS are thought to be due to the harmful effects of elevated cortisol levels. The treatment of CS is based on reducing the raised cortisol levels, either by removing the source of the increased production or by blocking the synthesis of cortisol in the adrenal. The aim is to reduce the mean level during the day to 300-400 nmol/L, equivalent to normal production (Internal Medicine 2nd edition, editors J Kumar and M L Clark chapter 16 pg. 815).
Cushing's disease occurs in many animal species as well as man. In dogs the disease is characterised by weight gain, lethargy, diabetes, coarse thickening of the hair, polyuria and polydipsia. It is perhaps a more common disease in certain breeds of dog than it is in humans.
In certain breeds of dogs changes in adrenal and/or gonadal hormone levels can cause a form of adult-onset alopecia, Alopecia X. The link of this disease with adrenal hormone abnormalities has been well established, with the condition also being called congenital adrenal hyperplasia, Cushing's-like syndrome and adult onset hyposomatotropism. Affected dogs are healthy except for hair and skin changes. Alopecia X occurs mostly commonly in the Nordic breeds, dogs such as pomeranians, chow chow, Irish water spaniels, husky and poodles. Alopecia usually develops in young adult dogs between 1 and 2 years of age and can occur in either sex. A symmetrical pattern of hair loss over the trunk and thighs is typical and may be associated with intense hyper-pigmentation. The hormonal abnormalities associated with Alopecia X vary between the breeds; altered steroidogenesis occurs in affected miniature poodles and Pomeranians with increased blood and urinary cortisol and 17 hydroxy progesterone (17 OHP) concentrations. In alopecic keeshonds there is an increased blood 17 OHP and oestradiol level. In alopecic chows and Irish water spaniels there are increased concentration of 17 OHP.
Horses, especially elderly horses, can also develop an equine variety of CS. This is characterised by polyuria, polydipsia, lethargy and peri-orbital fat deposits. A significant proportion of horses with CS also develop laminitis, a condition that affects the small bones of the feet and which can be notoriously difficult to treat. The aim of treatment in animals is the same as in humans and attempts to achieve a permanent suppression of the raised cortisol levels.
According to Nishizawa S, et al (Neurosurgery 1999 August; 45(2):239-44) the goal of surgical treatment for Cushing's disease is “endocrinological cure.” In this study postoperative endocrinological analysis was evaluated in 18 patients with Cushing's disease who underwent trans-sphenoidal surgery. Serum adrenocorticotropic hormone (ACTH) levels were measured by radioimmunoassay during the first week after surgery. One week after surgery, a test using corticotropin-releasing hormone (CRH) was performed on each patient to check the reserve function of normal ACTH-secreting cells. In eight patients, postoperative ACTH levels were below the measurable level of 1 week, and ACTH showed no response to the CRH test. In these patients serum ACTH and cortisol levels were kept in the normal range with a normal diurnal variation during long-term follow-up. These patients were defined as endocrinologically cured. In seven patients the ACTH level returned to within normal range on the day after surgery but ACTH was provoked by the CRH test. Five of these seven patients showed subsequent re-elevation of ACTH above the normal range. ACTH levels were never normalized in the remaining three patients, and medical treatments were unavoidable. The study's authors defined endocrinological cure in Cushing's disease as a lack of response of ACTH to the CRH test in the early post-operative stage and an unmeasurably low ACTH level in the week after surgery. Obtaining a normal range of ACTH level postoperatively was insufficient to define endocrinological cure.
An essential element of treatment has therefore been the complete eradication of the ACTH drive or the extirpation of the source of increased cortisol production. This nowadays is usually achieved by surgical removal of the adrenal glands or by destroying the pituitary lesion responsible for the increased ACTH production. If the increased ACTH is from an ectopic site the principle remains the same i.e. removal of the source of ACTH. For all such treatments to be successful there is a resulting sustained fall in cortisol levels and patients may be required to receive hormonal supplements.